Abstract A population-based study to investigate the epidemiological, genetic and clinical features of neurofibromatoses (NF) in Northern Finland was carried out between 1989–1996. The area concerned was that served by Oulu University Hospital, with a total population of 733 037. A total of 197 patients with neurofibromatosis type 1 (NF1), five with neurofibromatosis type 2 (NF2) and eight with segmental neurofibromatosis (NF5) fulfilling the diagnostic criteria were identified among several hundred patients examined on account of a possible NF diagnosis. The 197 NF1 patients came from 119 families. 77 of these cases were sporadic, 117 familial, and three were mothers of children suffering from NF1 who were themselves diagnosed as having segmental NF. The male/female ratio was 0.93 (95 males and 105 females). The geographical distribution of the patients roughly corresponded to that of the general population in the area. The overall prevalence of NF1 was 23/100 000, with a peak prevalence of 34/100 000 in the age group 10 to 19 years. The overall birth incidence of NF1 was estimated to be 27/100 000, with the highest figure, 37/100 000, recorded in the six-year period 1990–1995. The mean age at the time of diagnosis was 20 ± 16 years in the whole population and 6 ± 4 years in the children born in the 1980's. A new mutation was suspected in 49% of the NF1 cases (96/197), and a mutation rate of 4.37 ± 0.72 × 10-5 was obtained for the period 1960–1995. The relative fitness of the NF1 patients was 0.48, being reduced more in the affected males (0.24) than in the females (0.72). The mean maternal and paternal ages of the sporadic patients were 30 ± 6 and 33 ± 6 years, respectively, which is significantly higher than in the general population. Two cases with a deletion of the NF1 gene were identified, one encompassing the loci from EVI-20 to INT-38 and the other the INT-27 locus, representing 3% of the 66 cases analysed. In seven familial cases the parental origin of the new mutation could be verified and linkage studies showed that the oldest affected individual in the family had inherited the mutation from the father in 6/7 cases. In one family seven members in three generations were affected with a rare spinal neurofibromatosis, and a linkage to the NF1 gene was shown. Of these seven patients, four are included among the 197 studied here while the other three lived outside the area. The diagnostic features of the 164 NF1 patients aged from three months to 73 years who were examined clinically included café au lait spots (CLS) in 96% of cases, freckles in 87%, neurofibromas in 69%, plexiform neurofibromas in 20%, Lisch nodules in 70%, optic glioma (asymptomatic) in 20% and pseudarthrosis in 3%. 56% of the cases had an affected first degree relative. A plexiform neurofibroma was diagnosed in 33 individuals and this became a malignant peripheral nerve sheath tumour(MPNST) during the seven years of monitoring in 15% of cases (5/33). Hyperintense T2 lesions in a MRI scan of the brain were found in 94% of the children under the age of six years who had had such a scan (n = 17) and in 84% of those under 16 years (n = 50). Symptoms related to NF1 which needed medical intervention, rehabilitation or follow-up were diagnosed in about 2/3 of the cases, and in 38% of cases such medical problems of this kind had been treated before NF1 was actually diagnosed. All these findings emphasise the need for a multidisciplinary approach to the follow-up of neurofibromatoses.

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Abstract Imaging of the head and spine with CT and/or MRI was performed on 125 Northern Finnish NF1 patients to evaluate the CNS lesions in patients of different ages and their role in diagnosis and follow-up. Manifestations of NF1 in the head were more common in children than in adults. 77% of the children and 33% of the adults had T2 hyperintense brain lesions. Optic gliomas were present in 29% of the patients, in 44% of the children and 10 % of the adults. 8% of the patients had other intracranial tumours . Spinal lesions were seen in 75% of the patients. Hyperintense T2 lesions were most common in the age group of 5 to 9 years. During follow-up of the children, the lesions diminished in 25%, remained unchanged in 36%, showed mixed behaviour in 20% and disappeared in 10%. In 15% they increased in size and number. In one patient a malignant tumour developed at the site of a T2 lesion. Optic gliomas were located intraorbitally and/or prechiasmally in 94%, chiasmally and/or at the hypothalamus in 58% and in other optic areas in 14% of the patients. 52 % of the intraorbital gliomas were bilateral. The gliomas remained unchanged in 68% of the children and 50% of the adults. Other lesions included plexiform neurofibromas, sphenoid bone dysplasias and hydrops of the optic sheath. Optic glioma was more common in children with T 2 hyperintense brain lesions than without them. The other brain tumours included six astrocytomas, including an affected mother and her son. In one patient the astrocytoma regressed spontaneously. Hydrocephalus was seen in 5% of the patients. T2 hyperintense brain lesions were more common and numerous in macrocephaly; all macrocephalic children, but only 59% of the normocephalic children were affected. All children without T2 lesions were normocephalic. The brain measurements did not reveal any specific area to be responsible for macrocephaly. Spinal postural changes and dural ectasias were more common in adults. The spinal cord was affected in two patients. Spinal neurofibromas were seen in 19% of the children and 55% of the adults. Even young children may have severe manifestations. In one family a rare familial type of spinal neurofibromatosis (FSNF) was observed in four adults with bilateral spinal neurofibromas at all levels of the spine. Although both CT and MRI were valuable in CNS imaging, MRI proved to be the method of choice in detecting T2 hyperintense brain lesions, in evaluating the intracranial extent of optic gliomas and hydrops of the optic sheath and lesions of the spinal cord and nerves. MR imaging proved necessary for evaluating the extent of NF1 manifestations and helpful in the diagnosis, screening and follow-up of NF1 patients.

Indiana University-Purdue University Indianapolis (IUPUI) / Nearly 18% of children are diagnosed with developmental disabilities. Autism spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) are increasingly common developmental disabilities, but neither is well understood. ADHD and ASD are both prevalent in the genetic disorder Neurofibromatosis type 1 (NF1) which impairs the Ras-MAPK/ERK pathway through mutation of the neurofibromin gene (NF1+/−). More broadly, syndromic forms of developmental disorders are often caused by mutations of proteins in pathways interconnected with Ras including TSC1/2, FMR1, and SynGAP. Of NF1 patients, around 30-50% are diagnosed with ASDs and more than 60% with ADHD. These studies are the first to show that male mice haploinsufficient for the Nf1 gene (Nf1+/−) exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD. They exhibit hyperactivity and impulsivity in an open field, delay discounting task, and cliff avoidance reaction test, rescuable through treatment with the clinically effective ADHD drug, guanfacine (α2A adrenergic receptor agonist). Previous experiments in our lab identified social deficits including deficits in consolidation of social memory. Using optogenetics and awake behaving electrode recordings, we explored the role of the cortico-striatal-limbic circuitry in impulsivity and in social deficits in male Nf1+/− mice. Manipulation of the prefrontal cortex, nucleus accumbens, or basolateral amygdala through optogenetics rescued social deficits. These studies are the first to record brain activity in a preclinical model of NF1 during impulsive behavior, finding broad spectrum changes across slow, delta, theta, and gamma oscillatory frequencies and decreased synchrony of the prefrontal cortex and nucleus accumbens during a delay discounting task. Overall, Nf1+/− male mice with deletion of a single NF1 gene recapitulate cognitive phenotypes of NF1 patients and are a useful model system to identify alterations in neural circuitry associated with ASD and ADHD.

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from mutations in the tumor suppressor gene NF1. NF1 encodes the protein neurofibromin, which functions to negatively regulate p21Ras signaling. NF1 has a wide range of clinical manifestations, including vascular disease, which is characterized by neointima formation and subsequent vessel occlusion. Despite numerous clinical observations of NF1 vasculopathy, the pathogenesis of vascular lesion formation remains unclear. To determine the consequence of Nf1 haploinsufficiency in vascular disease, we generated an in vivo model for dissecting vascular lesion formation. In response to mechanical arterial injury, Nf1+/- mice have significantly enhanced neointima formation characterized by an accumulation of vascular smooth muscle cells (VSMCs) and excessive cellular proliferation and Ras activation. Further, using the pharmacological antagonist, imatinib mesylate, we identified that neointima formation in Nf1+/- mice was directly dependent on Ras signaling through either the platelet derived growth factor β receptor (PDGF-βR) and/or the C-kit receptor activation. These observations identify a molecular mechanism of neointima formation given that our group has previously demonstrated that Nf1+/- VSMCs have hyperactive Ras signaling through PDGF-βR activation and Nf1+/- bone marrow derived cells (BMDCs) have increased recruitment and survival in response to C-kit activation compared to WT controls. In order to dissect the cellular contribution to neointima formation, we utilized cre/lox technology and adoptive hematopoietic stem cell transfer techniques to genetically delete one allele of Nf1 in endothelial cells, VSMCs or BMDCs individually to test which cell lineage is predominant in NF1 vasculopathy. Surprisingly, in response to carotid artery injury, heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation. Specifically, Nf1 haploinsufficiency in BMDCs resulted in an infiltration of macrophages into the neointima, providing evidence of “vascular inflammation” as factor in NF1 vasculopathy. Further, we demonstrate for the first time that NF1 patients have evidence of chronic inflammation determined by increased concentrations of circulating monocytes and pro-inflammatory cytokines. In sum, we provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1+/- mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions.

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